Drug addiction continues to be a major medical and social problem. It is estimated that one million or more persons in the United States are currently addicted to heroin, with millions more worldwide. Cocaine addiction and alcohol dependence are frequent comorbid conditions in heroin addicts in addition to being major primary addictions. Many studies over the past thirty years have shown that these drugs disrupt physiologic systems, and that these disruptions may contribute to drug addiction and alcohol dependence and to relapse to drug or alcohol abuse following withdrawal and abstinence. Clinical observations suggest that individuals differ in their response to heroin, cocaine, and alcohol; however, little is known about specific underlying hereditary genetic factors which might influence individual susceptibility to the addictive properties of these substances. Studies also suggest that both common and distinct heritable factors account for the genetic variance in the susceptibility to the separate addictive diseases. We hypothesize that there is a heritable as well as environmental basis for the acquisition and persistence of, and relapse to, specific addictive diseases. In this R01 application we propose to expand and increase our existing collection of DNA and immortalized cell lines from individuals without and with opioid and related drug dependencies and psychiatric comorbidities. Two separate types of genetic analyses will be used to determine association and linkage. All study subjects will be extensively characterized with respect to the addictive diseases, medical history, family medical addictive disease history; psychiatric comorbidity, and psychological profile, as well as ethnic background. A hypothesis driven approach will be utilized for the discovery of unknown polymorphisms in genes known to be involved in the responses to drugs of abuse, using traditional and novel methods. Functional studies of variant gene products caused by polymorphisms we identify will be performed, since altered function of these proteins may be important in individual responses to drugs of abuse, individual differences in the development and persistence of addiction, or in relapse to addiction, as well as in many aspects of normal physiology in which that gene product is involved. A better understanding of the consequences of genetic contributions with respect to protection from, or susceptibility to, heroin addiction and related codependencies and comorbid conditions, could have enormous importance in both prevention and treatment of this problem.